The deleterious effects of Ca ionic entry into neurons has been speculated to be a final common pathway of cell death. However, a direct cause-effect relationship between Ca and neuronal death has been difficult to establish. Cells dying from any cause will accumulate Ca. The entry of Ca into neurons and the subsequent pathological changes associated with Ca entry consequently may be manifestations rather than causes of cell death. Recent work showing that extracellular Ca ionic activity becomes profoundly depressed in injured spinal cord and ischemic cerebral cortex prompted a new hypothesis on Ca mediated damage. We propose that the initial fall in extracellular Ca activity, resulting from the death of some cells in the tissue, increases the susceptibility of the surviving cells to Ca entry when extracellular Ca activity levels normalize and that this accounts for part of the secondary damage that has been observed in neural injury models. Such a phenomenon has been described in cardiac tissues. Dubbed Ca paradox, this phenomenon occurs when heart cells are perfused with Ca-free solutions for several minutes followed by the return to normal Ca-containing solutions. The cardiac cells die and undergo physiological, morphological, biochemical, and other changes. The evidence supporting a Ca paradox phenomenon in injured neural tissues is summarized. The therapeutic implications of Ca paradox in neural tissue injury are discussed.